Kidney transplantation is the treatment of choice for most causes of end stage renal disease, but remains encumbered by its requirement for chronic use of multiple immunosuppressive drugs to prevent rejection. These drugs are not completely effective as most recipients eventually lose allograft function due to indolent rejection and they are associated with serious metabolic, infectious, and neoplastic side effects. Two particular agents, calcineurin inhibitors and steroids, dominate the morbidity seen post transplant. As such, methods that lessen one's reliance on calcineurin inhibitors and steroids hold promise to improve the outcome of patients requiring a transplant. Over the past 4 years, a phase 2 clinical trial has been conducted under the FDA Orphan Products Development (OPD) Grant program investigating means of reducing the post transplant immunosuppressive burden. It investigated off-label use of approved drugs: alemtuzumab, belatacept and sirolimus. It has shown that use of a single intraoperative dose of alemtuzumab, followed by maintenance treatment with belatacept and sirolimus allows for transplantation without the use of chronic steroids or calcineurin inhibitors. The initial trial of20 patients were transplanted without graft or patient loss. Importantly, several patients were shown to be withdrawn from sirolimus and maintained on belatacept, avoiding all daily immunosuppressive drugs in lieu of a single monthly infusion free of off-target side effects. Mechanistic studies performed have shown that patients so-treated maintain their protective immune competence while gradually reducing their response toward donor. A rational mechanistically driven framework explaining the treatment effects has been developed, and a biomarker, Ki67, has been proposed as a means of following future patients within this framework. This application proposes a continuation of this trial, using the emerging mechanistic and clinical insights to refine the protocol and extend its use to a more generalized population. The proposed study has three Specific Aims. In Specific Aim 1, Objective 1: Patients transplanted under the original trial will continue to be followed, continuing their management to study the outcome of monotherapy belatacept, assess their formation of alloantibody, and perform 5 year surveillance biopsies to assess the stability of patients on this minimized immunosuppressive regimen. Objective 2: Patients on the original trial who remain on multidrug immunosuppression of their medication will continue to be weaned based on the existing trial parameters to achieve a monotherapy belatacept regimen. In Specific Aim 2, a simplified and more applicable follow-up trial will be initiated in 20 patients, expanding the inclusion criteria o include recipients of deceased donor kidneys, eliminating the randomization involving bone marrow infusion, and reducing the immunologic exclusions. This will test the regimen in a population that will better determine the generalizability of the findings. In Specific Aim 3, a strategy will be evaluated for immune management that predicates drug weaning on objective measures of homeostatic repopulation including flow cytometric assessment of Ki67. This will provide strong mechanistic correlates to the parent trial, and prospectively test the utility of a biomarker predicated on the biology of post-depletional homeostatic lymphocyte repopulation. It is hoped this trial will produce a relatively simple and generally applicable method for transplantation that substantially reduces the expense and morbidity of chronic immunosuppression.